tbuckley/cabot-search huggingface dataset:
Survival analysis of patients treated at oncology practices with more aggressive end-of-life practice patterns.
Authors: Maureen Canavan, Xiaoliang Wang, Mustafa Ascha, Rebecca A. Miksad, Timothy N Showalter, Gregory Sampang Calip, Cary Philip Gross, Kerin B. Adelson
Journal: Journal of Clinical Oncology (2023)

6562 Background: Despite national focus on measuring and reducing end-of-life (EOL) systemic treatment among cancer patients, recent studies show a consistently high use of systemic anticancer therapy (SACT) at the EOL, as well as a shift to more targeted therapies. A criticism of measures that focus on deceased populations is that they do not account for patients who received treatment at the same time in their disease trajectory and had a positive response to therapy. We sought to explore whether being treated at an oncologically aggressive (OA) practice (defined as higher practice-level EOL SACT treatment rates), was associated with a survival benefit among patients in six common cancer types. Methods: This survival analysis used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. We included all adult patients with a confirmed diagnosis of metastatic disease in breast (mBC), colorectal (mCRC), renal cell carcinoma (mRCC) or pancreatic cancer (mPanc), or advanced disease in non-small cell lung (aNSCLC), or bladder cancer (aUC), between 2015 and 2019. The primary exposures were the practice-level risk-standardized 30-day EOL SACT rates calculated among decedents. The primary outcome was real-world overall survival (rwOS) among all patients. Adjusted hazard ratios (aHR) for each quintile of increasing OA EOL SACT rates (Q2-Q5) were estimated using disease-specific Cox proportional hazard models (reference: Q1), adjusting for patient and practice-level factors. Bonferroni correction was applied to account for multiple comparisons. Results: A total of 78,446 patients from 144 practices were included in the analysis with most patients seen at less OA practices (Q1-Q2). Patients seen at most OA practices (Q5) were less likely to be &lt;65 (32.5% vs 38.9% in Q1), Black (6.3% vs 12.2%), have Medicare (5.9% vs 10.7%) or Medicaid (1.5% vs 4.1%). After adjusting for covariates, there was no statistically significant difference in rwOS between patients treated at the most (Q5) and the least OA practices (Q1; table). However, there was variation among the moderately OA practices. Patients with mPanc seen at moderately OA (Q2-Q4) had 12% to 19% lower hazards of deaths (aHR range 0.81-0.88), compared to those at the least OA practices (Q1), but these associations were not statistically significant (Bonferroni corrected p-values &gt;0.05). Conclusions: When using rates of SACT at EOL to define OA practices, patients treated at these practices do not have improved survival. [Table: see text]
The expression of PKM1 and PKM2 in benign and cancerous prostatic tissues.
Authors: Lin Li, Siyuan Cheng, Xiuping Yu
Journal: Journal of Clinical Oncology (2023)

e17058 Background: Prostate cancer (PCa) is the most diagnosed cancers in American men. After androgen deprivation therapy (ADT) fails, there is an increase in the aggressive neuroendocrine (NE) phenotype. Currently, there is no effective treatment for NE prostate cancer (NEPC). The metabolic reprogramming, one of the cancer hallmarks, regulates PCa progression and therapy resistance. However, the energy metabolism in NEPC has not been well studied yet. Pyruvate kinase (PK), catalyzing the final step of glycolysis, has PKM1, PKM2, PKL and PKR four isoforms. PKL and PKR are expressed in the liver and erythrocytes, respectively. Alternative splicing of PKM results in two isoforms, PKM1 and PKM2, which are expressed in most tissues. In prostate adenocarcinoma, loss of PKM1 promotes PCa progression whereas loss of PKM2 suppresses tumor growth. However, the expression pattern of PKM1 and PKM2 in NEPCa remains largely unknown. Methods: Immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR were conducted to examine the expression of PKM1 and PKM2 in both murine and human prostatic tissues. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE). Results: TRAMP is a widely used PCa mouse model. TRAMP mice develop prostatic intraepithelial neoplasia (PIN) and the tumors progress into NEPC following castration. We found that PKM1 expression was detected in normal prostate but not in the PIN lesions. In the TRAMP NEPC tumors, PKM1 expression was detected in the NE areas but not in the adjacent PIN lesions. Compared with the adjacent PIN, NEPC cells displayed lower PKM2 expression. Further, we examined the expression of PKM1 and PKM2 in human prostatic tissues including benign prostatic hyperplasia (BPH), low-grade adenocarcinomas (AdPCa), high-grade AdPCa, and NEPC. We found that in BPH, basal epithelial cells express both PKM1 and PKM2. In PCa, PKM1 was robustly expressed in the stromal cells but its expression was absent in the cancer cells in majority of the specimens examined except a small number of samples where low level of PKM1 was detected in the cancer cells. However, PKM1 expression was detected in 9 out of 12 NEPC samples and colocalized with NE marker chromogranin A. This co-expression was also detected in the NE cells scattered on the prostate adenocarcinoma tissues. As for PKM2, its expression was detected in all the samples examined. However, different from previous report, PKM2 expression levels did not correlate with cancer grade in this cohort. Conclusions: PKM1 is expressed in the basal epithelial cells of benign prostates, a small subset of prostate adenocarcinomas, and 75% NEPC tumors. PKM2 is expressed throughout prostate development, in both benign and cancerous prostate. However, PKM2 expression does not correlate with tumor grade.
Real-world outcomes by race in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Final analysis results from the informCLL registry.
Authors: Jacqueline Claudia Barrientos, Jeff Porter Sharman, Meghan E. Gutierrez, Linda Wu, Zaina P. Qureshi, Anat Raz, Vincent Girardi, Maoko Naganuma, Nilanjan Ghosh
Journal: Journal of Clinical Oncology (2023)

7536 Background: informCLL is a large, US-based, prospective, observational registry of pts with CLL/SLL initiating treatment (tx) in the era after approval of ibrutinib (Ibr). Here, we report real-world tx patterns and outcomes by race and line of therapy (LOT) from the final analysis of informCLL. Methods: Pts with CLL/SLL who initiated FDA-approved tx were enrolled between 10/2015 and 6/2019. Baseline characteristics, tx patterns, time to next tx (TTNT), OS, and safety are summarized by race (focus on Black and White pts) and LOT (first-line [1L] or relapsed/refractory [R/R], with focus on 1L). Results: Of 1459 eligible pts enrolled, 105 were Black (1L, n=58; R/R, n=47), 1323 were White (1L, n=779; R/R, n=544), and 31 were of other races (Asian [n=6], Native American [n=4], other/not reported [n=21]). Relative to White pts, 1L-treated Black pts were younger (median age 65 vs 70 y) and had worse performance status (ECOG status ≥1: 59% vs 50%), more advanced disease (Rai stage III-IV: 55% vs 46%), shorter time from diagnosis to 1L tx (median 7 vs 19 mo), and lower rates of del(17p) among tested pts (6% vs 13%). Across race, Ibr was the most common 1L tx (Black, n=29 [50%]; White, n=346 [44%]) followed by CIT (Black, n=25 [43%]; White, n=331 [42%]). With median follow-up of approximately 32 mo in 1L-treated pts, the estimated rate of freedom from next-line therapy at 36 mo was similar between Black and White pts across all-treated pts and among Ibr-treated subgroups (Table). Estimated 36-mo OS rates in all-treated pts were also similar by race, with a high OS rate observed among Ibr-treated Black pts (97% at 36 mo). In multivariate analyses (MVA) in 1L-treated pts, male gender, poorer ECOG status, and increased comorbidity burden were independent predictors of decreased OS while race was not associated with OS. In 1L Ibr-treated pts, the only factor associated with decreased OS in MVA was longer time from diagnosis to 1L tx. Rates of serious AEs and AEs leading to tx discontinuation appeared similar across race (Table). Conclusions: Although historical retrospective studies from the pre-novel agent era have shown poorer clinical outcomes among Black pts with CLL relative to non-Black pts, results from informCLL show similar or potentially improved outcomes, including OS, among 1L Ibr-treated Black pts relative to White pts. These results suggest that access to novel agents such as Ibr may in part overcome historical disparities in clinical outcomes by race in pts with CLL. Clinical trial information: NCT02582879 . [Table: see text]
Are enrollment criteria for phase II and III clinical trials in acute myeloid leukemia arbitrarily restrictive?
Authors: Andrew Hantel, Thomas Walsh, Dillon Clancy, Marlise Rachael Luskin, Daniel J. DeAngelo, Christopher S. Lathan, Gregory A. Abel
Journal: Journal of Clinical Oncology (2023)

6525 Background: Ethical clinical research requires fair subject selection and a favorable risk-benefit ratio. Enrollment criteria can unfairly exclude patients if they are not based in safety. There are few data regarding variability within criteria, which can also represent unfair exclusion, or for acute myeloid leukemia (AML). Methods: We assessed enrollment criteria use and variability for frontline phase II and III therapeutic AML trials from 2010-2019 listed on Clinicaltrials.gov. Drug safety profiles were obtained from protocols, publications, and FDA labels. FDA publications guided a standardized abstraction and coding process. Associations between criteria and safety profiles were identified using X 2 and t-tests. Regression modeling identified differences in infectious disease (ID) exclusion by sponsor adjusted for trial phase, year, size, and safety profiles. Results: 190 trials were eligible; 159 (84%) were phase II and 32 (17%) phase III. Trials were sponsored by the National Institutes of Health (NIH; 50; 26%), industry (109; 57%), and academic investigators (AI; 108; 57%). Exclusions and variability are shown in the table. ID exclusions were for HIV (96; 51%) and hepatitis B (60; 32%) and C (64; 34%). Older adults were considered as over 60 (42 trials; 39%), 65 (23; 21%), 70 (13; 12%), or 75 years (18; 17%). There was no association between QTc limits and the use of QTc prolonging drugs (criteria presence p=0.2; mean 450 vs 474 ms, p=0.3) or renal function limits and nephrotoxic drugs (presence p=0.2; mean 1.65 vs 1.67 ULN, p=0.8). Hepatitis B and C exclusions were associated with the use of drugs linked to viral reactivation (OR 2.1 [95% CI 1.1,3.9], 2.0 [95% CI 1.1,3.7]). This was not the case for HIV (OR 1.2 [95% CI 0.7,2.2]). Industry sponsorship was independently associated with hepatitis B and C exclusion (OR 3.0 [95% CI 1.2,7.3], 3.3 [95% CI 1.4,4.7]) and AI sponsorship with HIV exclusion (OR 2.5 [95% CI 1.4,5.5]). Conclusions: There is substantial variability in enrollment criteria for AML clinical trials. Many criteria are related to risks, but some exclusions and variability are not clearly based in safety. Avoiding arbitrary exclusions will likely enhance trial representativeness and enrollment rates. [Table: see text]
Association of neutrophil-lymphocyte ratio with survival in peripheral early-stage non–small-cell lung cancer after stereotactic body radiation therapy.
Authors: Karen Huang, Sharan Prasad, Sung Jun Ma, Han Yu, Austin Iovoli, Mark Farrugia, Elisabeth Dexter, Todd L. Demmy, Nadia Karen Malik, Anurag K. Singh
Journal: Journal of Clinical Oncology (2023)

e20547 Background: Prior studies have demonstrated that neutrophil-lymphocyte ratio (NLR) can predict overall survival in patients undergoing stereotactic body radiation therapy (SBRT) for multiple types of cancer. The role of neutrophil-lymphocyte ratio (NLR) as a predictor for survival in single fraction SBRT-treated non-small cell lung cancer (NSCLC) patients remains unclear. Methods: A single-institution database of peripheral early-stage NSCLC patients treated with SBRT from February 2007 to May 2022 was queried. Consecutive patients with peripheral early-stage NSCLC (T1-2N0M0) and a complete blood count within six months of the start of SBRT treatment were included. Patients treated with SBRT regimens of more than 3 fractions were excluded as these regimens were reserved for patients with centrally located lesions with higher risk of toxicity which could affect survival. Optimal threshold of neutrophil-lymphocyte ratio (NLR) was defined based on maximally selected rank statistics. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate outcomes. Results: A total of 286 patients (164 female [57.3%]; median [IQR] age 76 [69-81] years) were included for analysis with median follow up of 19.7 months. The median NLR was 3.06 ([IQR] 2.21-4.33). There were 15 local failures, 27 nodal failures, and 50 distant failures. On Cox multivariate analysis, as a continuous variable, NLR was shown to be an independent predictor of OS (adjusted hazards ratio [aHR] 1.06, 95% CI 1.02-1.10, p = 0.005; Figure 1) and PFS (aHR 1.05, 95% CI 1.01-1.09, p = 0.013; Figure 1). In addition, NLR was associated with DF (aHR 1.11, 95% CI 1.05-1.18, p &lt; 0.001; Figure 1). Maximally selected rank statistics determined 3.28 as the cutoff point of high NLR versus low NLR. These findings were confirmed upon propensity matching. Conclusions: Pretreatment NLR is an independent predictor for survival outcomes of peripheral early-stage NSCLC patients after SBRT. High NLR is associated with worse overall survival, progression-free survival, and distant metastasis. Pretreatment NLR levels should be tracked on trials for early-stage NSCLC patients.
Identifying small non-coding RNAs as biomarkers for cervical cancer.
Authors: Josephine Peitz, Arica Stockett, Kiranpreet Chawla, Diana N. Carvajal, Amy Plotkin, Paul Staats, Clement Adebayo Adebamowo, Sally Nneoma Adebamowo
Journal: Journal of Clinical Oncology (2023)

e17507 Background: Small non-coding RNAs (sncRNAs) that control post-transcriptional gene expression are attractive candidate molecular targets for cancer screening tests. We evaluated whether sncRNAs expression are markedly different in benign, precancerous, and cancerous cervical tissue. Methods: We examined the expression of six sncRNA species: circular RNAs (circRNAs) microRNAs (miRNAs), piwi-interacting RNA (piRNAs), small nuclear RNA (snRNAs), small nucleolar RNA (snoRNAs), and transfer RNA (tRNA), from archival formalin-fixed paraffin-embedded cervical specimen obtained from 172 women (74 benign, 58 high-grade squamous intraepithelial lesion (HSIL) and 40 invasive cervical cancer). We used DESeq2 to identify differentially expressed sncRNA molecules with adjusted p-value &lt; 0.05 and at least 2-fold up- or down-regulation. Results: Comparing benign to HSIL samples, we foundseveral statistically significant, differentially expressed sncRNAs: 906 circRNAs (*circ_0066810, p=3.76x10 -16 ), 87 miRNAs (*miR-149-5p, p=1.30x10 -14 ), 11 piRNAs (*piR_016945, p=8.32x10 -13 ), 32 snRNAs (*RNU1-17P, p=1.90x10 -10 ), 5 snoRNAs (*SCARNA18, p=1.35x10 -5 ), and 24 tRNA (*tRNA-Glu-TTC-8-1, p=6.45x10 -17 ). Comparing benign to invasive cervical cancer samples, we also foundseveral statistically significant, differentially expressed sncRNAs: 3,192 circRNAs (*circ_0123115, p=7.46x10 -50 ), 325 miRNAs (*miR-7-5p, p=6.72x10 -36 ), 82 piRNAs (*piR-hsa-27513, p=1.44x10 -15 ), 71 snRNAs (*RNU1-20P, p=1.37x10 -45 ), 52 snoRNAs (*SNORD95, p=1.68x10 -23 ), and 68 tRNA (*tRNA-Cys-GCA-9-3, p=1.01x10 -21 ). * Indicates the sncRNA with the smallest p-value, for each specie. Conclusions: Our results identify sncRNAs with potential utility of as diagnostic and prognostic biomarkers, and therapeutic targets for cervical precancer and cancer.
A pilot study to determine the effects of early palliative care integration on patients with newly diagnosed multiple myeloma.
Authors: Renato Verayo Samala, Jason Neil Valent, Wei Wei, Jasmine Crook, Sherry Fada
Journal: Journal of Clinical Oncology (2023)

e24118 Background: While multiple studies underscore the value of early palliative care (PC) involvement in patients suffering from cancer, particularly solid tumors, the effect of early integration on the care of patients with multiple myeloma is not as widely known. This study aims to obtain preliminary data on the effects of early PC involvement on patients with newly diagnosed symptomatic multiple myeloma. Methods: This is a pilot study with a prospective cohort design and based in the outpatient setting. Patients at least 18 years of age and within eight weeks of diagnosis were included. Each participant was seen by a PC specialist monthly for 12 months for ongoing symptom management and advance care planning. Quality of life was assessed using Functional Assessment of Cancer Therapy-General (FACT-G), plus the Multiple Myeloma Subscale (FACT-MM). Hospital Anxiety and Depression Scale (HADS) was used to estimate the number of participants with self-reported symptoms of depression and anxiety. Questionnaires were administered upon enrollment and every three months for 12 months. The percentage of participants who completed the study was assessed to determine the feasibility of this approach. Results: Of the twenty participants enrolled from January 2020 to November 2022, median age was 65 (range 40, 77), 15 (75%) were female, 15 (75%) were white and 11 (55%) had an Eastern Cooperative Oncology Group Performance Status score of 1. Eighty-five percent of participants completed assessment at three months, 65% at 6 months, 65% at 9 months, and 60% at 12 months. FACT-G total score was significantly higher (increased by 15.1 points) at 12 months compared to baseline (adjusted 95% CI: 2.2-28.1, adjusted p = 0.018). Functional well-being (FWB) subscale score was significantly higher (increased by 5.0 points) at 9 months compared to baseline (adjusted 95% CI: 0.5-9.5, adjusted p = 0.025), and at 12 months compared to baseline (adjusted 95% CI: 1.1-10.9, adjusted p = 0.012). Depression and anxiety scores did not significantly change over time. Conclusions: Improvement in quality of life was seen among patients with newly diagnosed symptomatic multiple myeloma after 12 months of early PC involvement. Monthly PC visits appeared to be feasible for these patients. Clinical trial information: NCT04248244 .[Table: see text]
Economic evaluation for the US of relatlimab and nivolumab (RELA+NIVO) versus nivolumab (NIVO) monotherapy in untreated advanced melanoma.
Authors: Osama Aqel, Ibrahim Alfayoumi, Yunrong Shen, Oiza Aliu, Syeda Hina Zaidi, Valeria Moreno-Rodriguez, Oluwayemisi O Ayoade, Hassan Alzahir, Jan Marco Kopecky, Salma Khattab, Mattie Snyder, Ivo Abraham
Journal: Journal of Clinical Oncology (2023)

9539 Background: The RELATIVITY-047 trial demonstrated longer median progression-free survival (PFS) with the combination of RELA+NIVO (10.1 months, 95% CI = 6.4 to 15.7) over NIVO (4.6 months, 95%CI = 3.4 to 5.6) in patients with untreated advanced melanoma (hazard ratio for progression or death = 0.75, 95%CI = 0.62 to 0.92). This economic evaluation aimed to estimate the cost-effectiveness/utility of RELA+NIVO vs. NIVO monotherapy in this setting. Methods: A two state partitioned survival model (PFS, progressed/death) was developed to compare costs and PFS outcome associated with both treatments. PFS curves were digitized and parametric functions fitted. A 5-year time horizon from a US payer perspective with a 3% discount rate/year was considered. Costs of treatment (average sales price), administration and monitoring parameters were derived from Centers for Medicare &amp; Medicaid Services databases; cost of adverse events (grade 3/4 with rate &gt;5%) were derived from prior advanced melanoma economic evaluations. Incremental costs, PFS life years (PFSLY), and PFS quality adjusted life years (PFSQALY) gained (g) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). A cost-effectiveness acceptability curve (CEAC) was plotted to determine the probability of either treatment to be cost-effective over the other at different willingness to pay (WTP) thresholds. Results: Exponential regression was used to extrapolate RELA+NIVO and NIVO survival curves. According to the result table shown below, the BCA (PSA) shows an incremental cost of RELA+NIVO over NIVO of $405,663 ($402,936), incremental PFSLY of 0.326 (0.325), and incremental PFSQALY of 0.260 (0.256). The BCA (PSA) ICERs indicated an additional $1,244,365 ($1,239,803) per PFSLY gained (g) and an additional $1,560,242 ($1,573,969) per PFSQALYg. The CEAC curve shows that RELA+NIVO treatment had a 50% probability of being cost-effective regimen at a WTP threshold value of $1,525,000 and 100% probability at a threshold of $3,050,000 or above. Conclusions: In the setting of advanced melanoma, this economic evaluation showed that RELA+NIVO is associated with improvement in LY and QALY, however, at a marked incremental cost, requiring a very high WTP threshold. [Table: see text]
GD2 and GD3 gangliosides as diagnostic biomarkers for all stages and subtypes of ovarian cancer.
Authors: Anna Jeter, Alba Galan, Arturo Papaluca, Ali Nejatie, Emad Matanes, Fouad Brahimi, Amber Yasmeen, Euridice Carmona, Kathleen Oros Klein, Sonja Billes, Ahmed E. Dawod, Prasad Gawande, Anne-Marie Mes-Masson, Celia Greenwood, Walter H. Gotlieb, H. Uri Saragovi
Journal: Journal of Clinical Oncology (2023)

e17604 Background: Ovarian cancer (OC) is the deadliest gynecological cancer, often diagnosed at advanced stages. A fast and accurate diagnostic method for early-stage OC is needed. The tumor marker gangliosides, GD2 and GD3, exhibit properties that make them ideal potential diagnostic biomarkers but they have never before been quantified in OC. We investigated the diagnostic utility GD2 and GD3 for diagnosis of all subtypes and stages of OC. Methods: This retrospective study evaluated GD2 and GD3 expression in biobanked tissue and serum samples from patients with invasive epithelial OC, healthy donors, non-malignant gynecological conditions, and other cancers. GD2 and GD3 levels were evaluated in tissue samples by immunohistochemistry (n=299), and in two cohorts of serum samples by quantitative ELISA. A Discovery Cohort (n=379) showed feasibility of GD2 and GD3 quantitative ELISA for diagnosing OC, and a subsequent Model Cohort (n=200) was used to train and cross-validate a diagnostic model. Results: GD2 and GD3 were expressed in tissues of all OC subtypes and FIGO stages but not in surrounding healthy tissue or other controls. In serum, GD2 and GD3 were elevated in patients with OC. A novel diagnostic model that included serum levels of GD2 and GD3 was superior to the standard of care (CA125, p&lt;0.001) at detecting OC, as well as, in early-stage (I/II) OC samples. Conclusions: GD2 and GD3 are high value candidates for building a novel diagnostic panel. A diagnostic model combining GD2 and GD3 quantification in serum had diagnostic power for all subtypes and all stages of OC, including early-stage. Further research exploring the utility GD2 and GD3 for diagnosis of OC is warranted. Future work will aim to validate these biomarkers in independent prospective studies. [Table: see text]